> It works by decreasing glucose production in the liver, increasing the insulin sensitivity of body tissues, and increasing GDF15 secretion, which reduces appetite and caloric intake.
Emphasis mine. So, looks like the actual aging deceleration is just the cliche, that it's healthy to not be overweight?
A principal mechanism of action of metformin is AMPK-dependenent inhibition of mTORC1 in the liver. [1] mTORC1 inhibition also occurs when fasted and when taking Rapamycin. Rapamycin has been floated many times as a life extension drug. [2]
mTOR is one of the major nutrient sensing pathways in the body, particularly sensitive to amino acids (especially methionine and leucine) but also to energy levels in general via AMPK. Inhibition of mTOR slows down cell division and induces autophagic flux -- further mTOR dysregulation is implicated in about 70% of cancers. It is an incredibly highly conserved pathway in everything from yeast to humans, and [m]TOR inhibition has been shown to dramatically extend life in basically everything that moves. I believe there's a life extension trial in humans under way around Rapamycin but I could be mistaken.
It acts as a very targeted partial starvation mimetic.
[edit] > that it's healthy to not be overweight?
This is separately also true. But what's neat about metformin is that generally diabetics on metformin are less likely to develop cancer than non-diabetics. [3] So it stands to reason that non-diabetics taking metformin would have even lower incidence of cancer no?
[edit] I find this stuff very cool, and I personally expect mTOR to be the next golden child after everyone gets on GLP-1s.
[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5299044/
I believe that these things work. But I for one don't want more years as a wage slave, particularly when coupled with anhedonia. Sure, I'll extract more value for my corporate overlords, but what's in it for me? For some definition a long life without any pleasure is an optimization, but I'd argue the validity of this definition.
I want a future where people aren't dying of cancer, cardiovascular disease, losing limbs and eyes to diabetes, getting strokes and where they're living long and healthy lives. I don't really care so much about the means. GLP-1s are the only proven non-surgical intervention that allows people to lose a clinically significant (>5%) amount of weight and keep it off long-term (>5 years).
Prior to Iodized salt, Switzerland was suffering from a rash of people with Goiter, which is disfiguring and decreases your quality of life, and also a large population with cretinism which causes stunted growth and mental retardation.
Then, they introduced iodized salt, and those issues which used to be somewhat prevalent only 100 years ago are practically nonexistent now.
https://swissfederalism.ch/en/100-years-salt-iodination-swit...
The hard way of finding out how bad polished white rice is for you - https://www.atlasobscura.com/articles/rice-disease-mystery-e...
There are many companies making different versions of this drug, I don't see why you think its some kind of conspiracy intended to control the masses, literally if the benefit is greater than the costs what is your issue with it?
https://www.fractyl.com/fractyl-health-demonstrates-signific...
https://recursiveadaptation.com/p/the-growing-scientific-cas...
> The consistency that I'm hearing from all across patient groups is gain of control, whereas previously, there was a loss of control… All of a sudden they're able to step back and say, 'oh, well I had this shopping phenomenon that was going on, gambling, addiction, or alcoholism, and all of a sudden, it just stopped,' -- Dr. Gitanjali Srivastava, Vanderbilt Medical Center
https://news.ycombinator.com/item?id=40357197 (comment from u/comova)
> 1. GLP-1 drugs appear to dramatically reduce addictive drive across substances. 2. GLP-1 drugs can reach vastly more patients than existing medications and they have positive mental health benefits for anxiety and depression. 3. This is our first ever opportunity to make a big dent in the addiction crisis, which kills 770,000 people a year between opioids, cigarettes, and alcohol.
If it's a net positive to my life what is the problem?
You have a very dismal view of the world, it is possible to enjoy one's work, or at least tolerate it, or work for yourself in the current economic system. Personally I appreciate the improved standard of living I have thanks to the efficiency of our profit driven system.
Immediately after going on metformin my appetite calmed. Slowly, over the next year, I lost 25 pounds. I did not try to diet. My BMI is now 23.7.
After a few months I started weight training. I changed my diet to lower carbs. I haven't lowered my HbA1c into a totally comfortable level (it is 5.6 and 5.7 and above is prediabetic). But I am better.
But before any of those changes, just the Metformin alone calmed my appetite. I can go hours without thinking about food. I am just less concerned. I feel normal.
Just as a data point, the last time I got Covid, it was quite mild. It's at least possible that the better metabolic health and weight loss had an impact.
In contrast, the evidence of any direct in vivo action of metformin on mTORC1 is dubious. In vitro studies may be of little relevance in this context.
Even indirect effects of metformin via AMPK activation are controversial.
A careful study by Keys and colleagues of a large Danish cohort of twins (2022)found no reduction in all-cause mortality by metformin treatment.
They point out that the highly influential Bannister et al. study (2014, pushed by a high profile TED presentation) has not been replicated despite a 10-year period in which to do so. Here is the link to the Keys paper that makes me highly skeptical about use of metformin to modulate aging rates.
https://pubmed.ncbi.nlm.nih.gov/36287641/
Could you highlight any strong in vivo studies on metformin targeting mTORC1 selectively or otherwise?
I am not quite sure what to make of this Cell paper yet.
In the NIA Interventions Testing Program (systematic studies of the impact of drugs on longevity) metformin has inly weak effects in males (p ~0.3) and no effect in females:
https://phenome.jax.org/itp/surv/Met/C2012
In contrast adding rapamycin work wonders (in mice).
found no reduction in all-cause mortality by metformin treatment.
Roughly speaking, they compared:
- people with diabetes that was treated with Metformin
- their twins who didn't have diabetes and were not taking Metformin
As far as I can tell, they didn't isolate the impact of metformin alone (vs the combined impact of having diabetes and taking metformin).
Have I misunderstood?
“individuals with Type 2 diabetes who initiated metformin monotherapy as their first-line treatment exhibit lower mortality over follow-up compared to the general population WITHOUT diabetes.” (emphasis added)
That is an exceedingly strong and apparent wrong claim. Mortality rates are worse among metformin treated subjects.
Of course there is no perfect control of the type we might want in principle (metaformin-treated non-diabetics or non-treated Type 2 diabetics).
However the first type of these case-controls studies has been done in genetically diverse mice by the NIA ITP team and the results are reasonable strong and negative.
My point is that you seem to be saying that the Keys study shows that metformin doesn't increase life expectancy. I am basing this understanding on two things you wrote:
"found no reduction in all-cause mortality by metformin treatment"
"Mortality rates are worse among metformin treated subjects."
But the Keys study does not show that Metformin doesn't increase life expectancy (or reduce all-cause mortality). It shows that Metformin isn't enough to counteract the impact (on lifespan) of diabetes. But it seems to say nothing about whether people (whether diabetic or not) would live longer with metformin or without.
I realize the Keys study isn't the only piece of research in this area. But the topic of my original comment (and this one) are simply that particular study, and what you say it shows.
If I have misunderstood anything I am happy to be corrected/educated.
A person (and the processes in their body) goes through cycles on a daily and long-term basis. One is not constantly eating, exercising, and growing.
Muscle mass and strength are not the same thing, though they are highly correlated. I believe most studies on the elderly use measures like grip strength, which is a proxy for frailty.
The elderly don't have the same capacity for growth or energy. However, they can avoid wasting away by remaining active. They certainly benefit from autophagy as it clears senescent cells. Perhaps this shift is the body's way of reducing the risk of cancer.
As an aside, a curious data point is that men have shorter lifespans than women on average. There are likely several reasons for this, but I wonder if this has to do with the hormonal effect on mTOR. Perhaps our ability to grow is finite, and excessive activation of mTOR "runs out the clock" faster.
TL;DR: It's a balancing act.
This video actually helped to motivate me to get into meal prepping, and significant weight loss.
I've been researching this topic (in the context of keto) on my own for the last 10 years or so and can say that nothing he said is wrong. I don't know why all of this isn't common knowledge at this point, other than the signal just gets lost in the noise between dry research papers and fad-pushing articles and products.
Your mercury load is higher if you eat twice as much fish, meanwhile the benefits of eating some fish are proportionally higher than eating a lot of fish. You want small portions of a lot of things, not large portions nor narrow selection.
As a SWE/EE I tend to look at things through that lens, and it seems like most processes in the body are AC coupled. DC signals tend to get filtered out and not recognized properly. Lower calorie diets and fasting convert mTOR agonism from a DC signal to an AC signal and it's the periodic alternation of modes that keeps you healthy. Periods where you can tear down the broken and periods where you can rebuild.
Another example, people look at stress hormone cortisol as leading to central adiposity in the context of insulin resistance. This is fundamentally backwards - cortisol is a potent insulin antagonist, it's a catabolic hormone that prevents insulin secretion, disrupts insulin signaling and mobilizes stored fat. The problem is when it's constantly elevated (DC signal) it stops working, and the opposite happens.
mTOR inhibition also modulates the immune system and suppresses hyperimmunity. This reduces inflammation (via Hypoxia-indidible factor 1-alpha / HIF1A and several downstream processes). Which explains why metformin reduces inflammation too. Even more interesting is that inhibition of mTOR in the AMPK-mTOR-HIF1A pathway makes vaccines significantly less effective.
[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9329718/
[2] https://www.nobelprize.org/prizes/medicine/2016/press-releas...
Maybe try 10mg doses but the 5g should do it.
Inflammation bitch slap.
Is it two antagonistic factors that require us to meet in the middle to find the healthiest balance or is there something else at play?
My first quibble is: honestly an 8 hour window for eating is pretty large, that's like, late breakfast, lunch and dinner. Is that fasting? It seems like kind of a normal eating schedule.
My first thought when I read something like this is "why would it be severely detrimental" and the first response is "the kind of people who are overweight are the ones who are going to be trying new diets to lose weight, and being overweight in the first place is severely detrimental to lifespan." Controlling for that, there may be something further confounding, for instance.
People skip breakfast all the time, and skipping breakfast leads to a 60% increase cancer risk. Peter Attia has a writeup on this [1]. Turns out, the people who skip breakfast are far less health conscious. People who skipped breakfast were 3X as likely to smoke. As he says, 'health and lifestyle characteristics between groups can either mask or exaggerate the association between frequency of breakfast consumption and mortality.'
I'd be very surprised if a kinda normal ish eating schedule led to a materially worse outcome when properly controlled. But proper control is damn near impossible in nutrition studies.
[1] https://peterattiamd.com/does-skipping-breakfast-increase-th...
Even worse, they define, "time-restricted eating" as being up to 12 hours!
>Time-restricted eating, a type of intermittent fasting, involves limiting the hours for eating to a specific number of hours each day, which may range from a 4- to 12-hour time window in 24 hours.
> The average reduction in blood pressure was 37/13 mm Hg, with the greatest decrease being observed for subjects with the most severe hypertension. [2]
It's probably just a poor job of controlling variables in the study.
Are typical monkeys obese like typical Americans?
Essentially: put them in small cages for years, give them a nearly unlimited supply of food, and give them nothing to do. Terrible.